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Chemical Compound Review

PYRROLIZIDINE     2,3,5,6,7,8-hexahydro-1H- pyrrolizine

Synonyms: SureCN35282, CHEBI:64950, HSDB 4300, NSC-90874, AC1L1ZUL, ...
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Disease relevance of HSDB 4300

  • The toxicity of macrocyclic pyrrolizidine alkaloids in the livers of man and animals has been attributed to the formation of reactive pyrroles from dihydropyrrolizines [1].
  • The results indicate that DHH is responsible for some, possibly most, of the carcinogenicity of the parent pyrrolizidine alkaloids and also stimulates the earlier and more rapid development of renal and vascular diseases normally associated with aging in rats [2].
  • When dehydroheliotridine (DHH), a pyrrolizidine alkaloid metabolite with bifunctional alkylating and antimitotic activities, was administered to a hooded strain of rats by ip injection, the incidence of tumors, excluding interstitial cell tumors, was significantly greater than that in saline-injected controls [2].
  • An infant with documented hepatic veno-occlusive disease due to ingestion of pyrrolizidine alkaloids is presented [3].
  • We hypothesize that this change is analogous to the hypertrophy and mitotic inhibition that occurs in the liver of animals treated with hepatotoxic pyrrolizidine alkaloids [4].

Psychiatry related information on HSDB 4300

  • Most progeny are sired exclusively by one male, the larger one, irrespective of parental age, male pyrrolizidine alkaloid content, mating order, between-mating interval, or duration of copulation [5].
  • In order to develop drugs effective against Alzheimer's disease, we synthesized a series of aniline derivatives having a characteristic cyclic amine, 1-azabicyclo[3.3.0]octane ring, and evaluated their binding affinity for the central muscarinic cholinergic receptor [6].

High impact information on HSDB 4300


Chemical compound and disease context of HSDB 4300


Biological context of HSDB 4300


Anatomical context of HSDB 4300

  • These studies suggest that the hepatocarcinogenicity of pyrrolizidine alkaloids can be better explained by their strong selection (promotion) influence on initiated hepatocytes, rather than by their very weak initiating activity [21].
  • Monocrotaline pyrrole (MCTP), a metabolite of the pyrrolizidine alkaloid monocrotaline, is thought to initiate damage to pulmonary endothelial cells resulting in delayed but progressive pulmonary interstitial edema, vascular wall remodeling, and increasing pulmonary hypertension [22].
  • They were given 2 doses of the pyrrolizidine alkaloid retrorsine (30 mg/kg, i.p.), 2 weeks apart, followed 2 weeks later by transplantation of 2 x 10(6) hepatocytes (via the portal vein), freshly isolated from a normal congeneic DPPIV+ donor [23].
  • A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay [24].
  • Na+/K(+)-adenosine triphosphatase activity of pulmonary arteries after intoxication with the pyrrolizidine alkaloid, monocrotaline [25].

Associations of HSDB 4300 with other chemical compounds

  • Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine [21].
  • Australine [(1R,2R,3R,7S,7aR)-3-(hydroxymethyl)-1,2,7-trihydroxypyrrolizid ine] is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis [Molyneux et al. (1988) J. Nat. Prod. (in press)] [26].
  • Administration of monocrotaline, a pyrrolizidine alkaloid, to male Sprague-Dawley rats for up to three weeks increased dry lung weights by 64% and reduced the specific activity of lung angiotensin-converting enzyme activity by 64% [27].
  • The gender differences in the in vitro microsomal metabolic activation of hepatotoxic clivorine, a representative naturally occurring hepatotoxic otonecine type pyrrolizidine alkaloid, in Sprague-Dawley rats and their relation to the gender differences in susceptibility to clivorine intoxication were reported in the present study [28].
  • The association of radiolabeled monocrotaline pyrrole (DHM) with red blood cell (RBCs) ghosts, globins, and heme was examined to determine their role in the transport and stabilization of this hepatic produced putative toxic metabolite of the pyrrolizidine alkaloid monocrotaline (MCT) [29].

Gene context of HSDB 4300

  • These observations suggested the potential involvement of the male-specific cytochrome P-450 UT-A and the P-450 PCN-E in the metabolism of this pyrrolizidine alkaloid [30].
  • Under oxidative conditions, reduction of the N-oxide to pyrrolizidine alkaloid is inhibited and while under hypoxic conditions, DHP formation is dramatically decreased [31].
  • These studies document the effects of pyrrolizidine alkaloid clivorine on the MAPK cascade and on the growth of human normal liver L-02 cells for the first time, which may be a possible reason for the toxic effects observed in those plants containing pyrrolizidine alkaloids [32].
  • Moreover, another pyrrolizidine alkaloid monocrotaline had no effect on phosphorylation of p38 MAP Kinase in L-02 cells [32].
  • A series of naphthalene derivatives substituted with the 1-azabicyclo[3.3.0]octane ring were also synthesized and muscarinic M1 and M2 receptor binding affinity determined [33].

Analytical, diagnostic and therapeutic context of HSDB 4300


  1. trans-4-Hydroxy-2-hexenal: a reactive metabolite from the macrocyclic pyrrolizidine alkaloid senecionine. Segall, H.J., Wilson, D.W., Dallas, J.L., Haddon, W.F. Science (1985) [Pubmed]
  2. Neoplasia and chronic disease associated with the prolonged administration of dehydroheliotridine to rats. Peterson, J.E., Jago, M.V., Reddy, J.K., Jarrett, R.G. J. Natl. Cancer Inst. (1983) [Pubmed]
  3. Hepatic veno-occlusive disease due to pyrrolizidine (Senecio) poisoning in Arizona. Stillman, A.S., Huxtable, R., Consroe, P., Kohnen, P., Smith, S. Gastroenterology (1977) [Pubmed]
  4. Changes in type II cell populations in monocrotaline pneumotoxicity. Wilson, D.W., Segall, H.J. Am. J. Pathol. (1990) [Pubmed]
  5. Postcopulatory sexual selection in an arctiid moth (Utetheisa ornatrix). LaMunyon, C.W., Eisner, T. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. Synthesis and muscarinic activity of novel aniline derivatives with a 1-azabicyclo[3.3.0]octane moiety. Suzuki, T., Oka, M., Maeda, K., Furusawa, K., Uesaka, H., Kataoka, T. Chem. Pharm. Bull. (1999) [Pubmed]
  7. Dehydroretronecine-induced skin tumors in mice. Johnson, W.D., Robertson, K.A., Pounds, J.G., Allen, J.R. J. Natl. Cancer Inst. (1978) [Pubmed]
  8. Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition. Deleve, L.D., Wang, X., Tsai, J., Kanel, G., Strasberg, S., Tokes, Z.A. Gastroenterology (2003) [Pubmed]
  9. Homospermidine synthase, the first pathway-specific enzyme of pyrrolizidine alkaloid biosynthesis, evolved from deoxyhypusine synthase. Ober, D., Hartmann, T. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  10. Bax-mediated apoptosis in the livers of rats after partial hepatectomy in the retrorsine model of hepatocellular injury. Gordon, G.J., Coleman, W.B., Grisham, J.W. Hepatology (2000) [Pubmed]
  11. Formation of cyclic adducts of deoxyguanosine with the aldehydes trans-4-hydroxy-2-hexenal and trans-4-hydroxy-2-nonenal in vitro. Winter, C.K., Segall, H.J., Haddon, W.F. Cancer Res. (1986) [Pubmed]
  12. Toxicity and pharmacokinetics of a pyrrolizidine alkaloid, indicine N-oxide, in humans. Kovach, J.S., Ames, M.M., Powis, G., Moertel, C.G., Hahn, R.G., Creagan, E.T. Cancer Res. (1979) [Pubmed]
  13. Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine. Laconi, E., Sarma, D.S., Pani, P. Carcinogenesis (1995) [Pubmed]
  14. Pulmonary heart disease induced by disenecioyl dehydroretronecine: a semisynthesis pyrrolizidine alkaloid pyrrole. Shumaker, R.C., Raczniak, T.J., Johnson, W.D., Allen, J.R. Proc. Soc. Exp. Biol. Med. (1977) [Pubmed]
  15. Effects of taurine and guanidinoethane sulfonate on toxicity of the pyrrolizidine alkaloid monocrotaline. Yan, C.C., Huxtable, R.J. Biochem. Pharmacol. (1996) [Pubmed]
  16. Deacetylclivorine: a gender-selective metabolite of clivorine formed in female sprague-dawley rat liver microsomes. Lin, G., Tang, J., Liu, X.Q., Jiang, Y., Zheng, J. Drug Metab. Dispos. (2007) [Pubmed]
  17. Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline. Petry, T.W., Bowden, G.T., Huxtable, R.J., Sipes, I.G. Cancer Res. (1984) [Pubmed]
  18. Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine. Laconi, E., Oren, R., Mukhopadhyay, D.K., Hurston, E., Laconi, S., Pani, P., Dabeva, M.D., Shafritz, D.A. Am. J. Pathol. (1998) [Pubmed]
  19. Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats. Gordon, G.J., Coleman, W.B., Grisham, J.W. Am. J. Pathol. (2000) [Pubmed]
  20. DNA minor groove alkylating agents. Denny, W.A. Current medicinal chemistry. (2001) [Pubmed]
  21. Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine. Hayes, M.A., Roberts, E., Farber, E. Cancer Res. (1985) [Pubmed]
  22. Prolonged cell-cycle arrest associated with altered cdc2 kinase in monocrotaline pyrrole-treated pulmonary artery endothelial cells. Thomas, H.C., Lamé, M.W., Morin, D., Wilson, D.W., Segall, H.J. Am. J. Respir. Cell Mol. Biol. (1998) [Pubmed]
  23. Direct hyperplasia does not enhance the kinetics of liver repopulation in a new model of hepatocyte transplantation in the rat. Pani, P., Laconi, S., Pillai, S., Scintu, F., Curreli, F., Shafritz, D.A., Laconi, E. J. Hepatol. (1999) [Pubmed]
  24. Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists. Becker, D.P., Flynn, D.L., Moormann, A.E., Nosal, R., Villamil, C.I., Loeffler, R., Gullikson, G.W., Moummi, C., Yang, D.C. J. Med. Chem. (2006) [Pubmed]
  25. Na+/K(+)-adenosine triphosphatase activity of pulmonary arteries after intoxication with the pyrrolizidine alkaloid, monocrotaline. Shubat, P.J., Bowers, R.J., Huxtable, R.J. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  26. Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing. Tropea, J.E., Molyneux, R.J., Kaushal, G.P., Pan, Y.T., Mitchell, M., Elbein, A.D. Biochemistry (1989) [Pubmed]
  27. Changes in angiotensin-converting enzyme activity in lungs damaged by the pyrrolizidine alkaloid monocrotaline. Lafranconi, W.M., Huxtable, R.J. Thorax (1983) [Pubmed]
  28. Gender differences in microsomal metabolic activation of hepatotoxic clivorine in rat. Lin, G., Cui, Y.Y., Liu, X.Q. Chem. Res. Toxicol. (2003) [Pubmed]
  29. Association of dehydromonocrotaline with rat red blood cells. Lamé, M.W., Jones, A.D., Morin, D., Wilson, D.W., Segall, H.J. Chem. Res. Toxicol. (1997) [Pubmed]
  30. Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver. Williams, D.E., Reed, R.L., Kedzierski, B., Dannan, G.A., Guengerich, F.P., Buhler, D.R. Drug Metab. Dispos. (1989) [Pubmed]
  31. Human liver microsomal reduction of pyrrolizidine alkaloid N-oxides to form the corresponding carcinogenic parent alkaloid. Wang, Y.P., Yan, J., Fu, P.P., Chou, M.W. Toxicol. Lett. (2005) [Pubmed]
  32. Pyrrolizidine alkaloid clivorine inhibits human normal liver L-02 cells growth and activates p38 mitogen-activated protein kinase in L-02 cells. Ji, L.L., Zhao, X.G., Chen, L., Zhang, M., Wang, Z.T. Toxicon (2002) [Pubmed]
  33. Synthesis and muscarinic activity of a series of quinolines and naphthalenes with a 1-azabicyclo[3.3.0]octane moiety. Suzuki, T., Usui, T., Oka, M., Suzuki, T., Kataoka, T. Chem. Pharm. Bull. (1998) [Pubmed]
  34. Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes. Oren, R., Dabeva, M.D., Karnezis, A.N., Petkov, P.M., Rosencrantz, R., Sandhu, J.P., Moss, S.F., Wang, S., Hurston, E., Laconi, E., Holt, P.R., Thung, S.N., Zhu, L., Shafritz, D.A. Hepatology (1999) [Pubmed]
  35. Restoration of serum albumin levels in nagase analbuminemic rats by hepatocyte transplantation. Oren, R., Dabeva, M.D., Petkov, P.M., Hurston, E., Laconi, E., Shafritz, D.A. Hepatology (1999) [Pubmed]
  36. Angiotensin converting enzyme activity and evolution of pulmonary vascular disease in rats with monocrotaline pulmonary hypertension. Kay, J.M., Keane, P.M., Suyama, K.L., Gauthier, D. Thorax (1982) [Pubmed]
  37. Dynamic pH junction-sweeping capillary electrophoresis for online preconcentration of toxic pyrrolizidine alkaloids in Chinese herbal medicine. Yu, L., Li, S.F. Electrophoresis (2005) [Pubmed]
  38. Crosslinking of DNA by dehydroretronecine, a metabolite of pyrrolizidine alkaloids. Reed, R.L., Ahern, K.G., Pearson, G.D., Buhler, D.R. Carcinogenesis (1988) [Pubmed]
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